Protein docking algorithms are designed to simulate interactions between proteins and small molecules to thereby predict bound conformation of protein-ligand complexes. Usually, docking programs are used to determine binding modes of inhibitors bound to active sites of enzymes. Given a protein structure, docking can be a powerful tool for screening compounds and has become an essential component in the field of computer-aided drug design.
A simulation of the binding phenomena of proteins and ligands requires two main components. A conformational search, with which one scans the conformational space of protein-ligand complex, encompasses a great number of algorithms that have been implemented in docking programs over the years. Examples are fast shape matching, genetic algorithms, simulated annealing, and Monte Carlo simulations. The other component of docking is scoring that scores protein-ligand binding structures in order of possibility. For the scoring, detailed description of atomic interactions between a protein and a ligand is needed. The scoring usually uses force field-based molecular mechanical calculations with some auxiliary scoring components to rank the generated poses. Scoring can be divided into three categories: empirical, knowledge-based, and physics-based. Among these, the physics-based scoring uses energy functions as a main component. However, this energy function is primarily based on a force field and thus cannot take into account of quantum effects. There are some instances for which accounting for quantum effect in docking might be important; one may be a case when electron transfer takes place. There are numerous examples among biological processes in which this phenomenon can be observed. In metalloproteins, charge transfer could occur between ligand and metal atoms as well as between protein and metal atoms. Therefore, it seems necessary to incorporate quantum mechanical (QM) calculations in docking for these proteins.
Hybrid quantum mechanical/molecular mechanical (QM/MM) methods have become a standard tool for the description of large molecular systems, in which QM level calculations are needed for parts of the system. A typical example of such systems can be an enzyme, since it is a large biomolecule but a small region thereof is involved in catalytic activities. All QM/MM methods are developed to treat quantum mechanically the part of the system that undergoes the most important electronic changes during a reaction or upon binding a substrate and the rest of the system by molecular mechanics.